Most 3D homology models of therapeutically relevant GPCRs are conceived to design, from a training set of reference compounds, in situ fingerprints of interaction able to forecast the structure and efficiency of new potent drugs. Achieving the best prediction of structure-based qualitative 3D pharmacophores or quantitative structure-activity models requires a reliable correlation between in vitro and in silico amino acid residues found to be specifically bound by high-affinity ligands....

Several knockout mouse models suggest a relationship between 5-HT and epilepsy. The audiogenic seizures syndrome is the first known defect caused by genetic manipulation of a 5-HT receptor subtype this provides a robust model for examination of serotonergic mechanism in epilepsy. Mutant mice lacking the 5-HT2C receptor subtype are extremely susceptible to audiogenic seizures and are prone to spontaneous death from seizures, suggesting that serotonergic neurotransmission, mediated by 5-HT2C...

The use of anatomo-functional markers, without precisely addressing cellular mechanisms of action of pharmacological compounds, gives a picture of the effects of drugs in a tissue. It is interesting to look at the data concerning 5-HT2C receptors in the basal ganglia where all modalities of interaction of 5-HT2C receptors may occur. Several studies have reported that 5-HT2C receptor stimulation may affect the expression of the proto-oncogene c-Fos in the brain. In basal ganglia, the effect is...

After the discovery of the importance of 5-HT2A receptor blockade (inverse agonism), initiated by research to uncover the mechanism of action of clozapine, which has multiple receptor affinities, interest focused on other clozapine high affinity binding sites, including the 5-HT2C receptor. The 5-HT2C receptor was proposed to be an important site of action of atypical antipsychotic drugs by a number of investigators (Canton et al. 1990 Cussac et al. 2000 Duinkerke et al. 1993a Herrick-Davis et...

Another interesting application of the data regarding the functional role of 5-HT2C receptors in the basal ganglia is the possible use of 5-HT2C receptor antagonists in the treatment of Parkinson disease (Fox and Brotchie 1999 Nicholson and Brotchie 2002 Di Giovanni et al. 2006). The neural mechanisms underlying the generation of Parkinsonian symptoms are thought to involve reduced activation of primary motor and premotor cortex and supplementary motor areas, secondary to overactivation of the...

Several groups examined RNA editing status of HTR2C in the brains of patients with mental disorders (Table 8.2). Due to the difference of technologies used and limited number of brain samples, the results are inconsistent across studies. In the early studies, Niswender et al. reported no significant alterations of RNA editing in patients with MD or SZ (Niswender et al. 2001). They examined RNA editing status of A, C, and D sites by a primer-extension-based method, yielding quantitative editing...

Opioid agonists such as heroin and morphine activate midbrain dopaminergic neurons and elevate extracellular levels of DA in striatal regions. The rewarding effects of opioids may depend in part on dopaminergic systems, although there is clear evidence of DA-independent mechanisms as well (Laviolette et al. 2002 Pettit et al. 1984 van Ree et al. 1999). The indirect dopaminergic effect of opioids can be altered by 5-HT2C receptor ligands. The agonist MK212 inhibited the increase in extracellular...

Among monoamines, the 5-HT control of adult neurogenesis has been the most largely investigated, notably when studying the consequences of serotonergic antidepressants. Indeed, chronic increases in extracellular level of 5-HT by selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, or paroxetine have repeatedly been shown to increase hippocampal neurogenesis in basal conditions and reverse the suppressive effects of stress or treatments associated with stressful events...

The 5-HT2C receptor (termed 5-HTlC receptors before 1994 see Hoyer et al. 1994) belongs to the seven transmembrane G-protein-coupled receptor family. It is located exclusively within the central nervous system (CNS) with no messenger ribonucleic acid (mRNA) detected in heart, lungs, intestine, or kidney (Julius et al. 1988). Numerous studies have demonstrated a widespread and similar distribution of the 5-HT2C receptor subtype in rat, monkey, and human brains. The highest concentration is...

Idzikowski et al. (1986) characterized for the first time the effect of acute administration of ritanserin 10 mg on nocturnal sleep in healthy subjects. Administration of the 5-HT2A 2C receptor antagonist in the morning (8 00 am) significantly increased SWS (stages 3 and 4) and reduced stage 2 sleep. REM sleep was also suppressed when the compound was given in the evening (10 30 pm). Idzikowski et al. (1987) investigated also the effect of repeated morning administration of ritanserin 10 mg on...

There are conflicting data on the effect of the acute administration of mCPP, a mixed 5-HT2A 2C agonist, to patients with schizophrenia, with one study reporting a decrease in psychotic symptoms (Kahn et al. 1992) three others, a mild exacerbation of positive symptoms (Iqbal et al. 1991 Krystal et al. 1993) and two, no significant effect (Maes and Meltzer 1996 Koreen et al. 1997). The reasons for these discrepancies are unclear. It is not related to route of administration, severity of...

Several compounds that are clinically effective antidepressants are potent 5-HT2C antagonists (Millan 2006). Nefazodone, trazodone, and remeron all block 5-HT2C receptors however, their pharmacological profile also encompasses blockade of 5-HT2A receptors as well as histamine 1 and alpha 2 receptors (Hyttel 1982). Agomelatonine is a potent 5-HT2C antagonist that has been shown to be effective in treatment of major depression. However, this compound also activates melatonin receptors, which...

Splice variants, lacking the full complement of TMDs, have been described for many different GPCR. These truncated receptors have been reported to have a dominant negative effect on wild-type receptor function through dimerization, resulting in trapping of wild-type receptors in the ER (Benkirane et al. 1997 Karpa et al. 2000 Grosse et al. 1997). Therefore, heterodimerization between wild-type receptors and splice variants may play an important role in normal physiological regulation of...

Central serotonergic systems have long been appreciated to have key roles in the regulation of feeding and body weight (for review, see Lam and Heisler 2007 Nelson and Gehlert 2006 Heisler et al. 2003). Studies of mutant mice with functional alterations of 5-HT2CR activity have elucidated some of the mechanisms underlying this important regulation. In the hypothalamus, 5-HT2CRs are prominently expressed on POMC-containing neurons of the ventrolateral arcuate nucleus (Wright et al. 1995...

The pharmacological actions and physiological effects of nicotine are complex. It is widely accepted that the reinforcing effects of nicotine are mediated in part by interactions between nicotinic acetylcholine receptors (nAChRs), GABA, glutamate, and DA in the VTA (for reviews, see Markou 2008 Di Matteo et al. 2007). A major neurochemical event that is involved in the behavioral effects of nicotine, including locomotor activity and reinforcement, is indirect activation of mesolimbic DA neurons...

Typical and atypical antipsychotic drugs bind to a wide variety of CNS receptors including the 5-HT2A and 5-HT2C receptors. Thus, it seems pertinent to analyze the effects of antipsychotic drugs on sleep variables and the mechanisms involved in their actions on sleep and W. It should be noted that Monti and Monti (2004) and Winokur and Kamath (2008) have provided detailed reviews of work carried out in this area. Our analysis will be limited to the effects on sleep variables of the typical...

Substantial evidence indicates that the mesolimbic pathway, particularly the dopaminergic system innervating accumbal areas, is implicated in the reward value of both natural and drug reinforcers, such as sexual behavior or psychostimulants, respectively (Koob 1992 Di Chiara and Imperato 1988 Salamone et al. 2007 Spanagel and Weiss 1999). The fact that drugs of abuse act through different cellular mechanisms leads to the possibility that their effects on DA release could be modulated...

The role of 5-HT in the control of appetite on the structure of rodent feeding behavior were first examined in a series of studies using the 5-HT releasing and reuptake-inhibiting drug fenfluramine (Blundell 1977). Fenfluramine produced reductions in caloric intake that corresponded to changes in feeding behavior normally brought about by ingestion, rather than hyperactivity, sedation, or malaise. Measurements Fig. 17.1 Functional divergence in 5-HT2C receptor pathway. Serotonin (5-HT) inhibits...

There are three commonly used models for antipsychotic activity blockade of conditioned avoidance response, antagonism of locomotor activity produced by amphetamine or the N-methyl-d-asparate (NMDA)-receptor antagonists, phencyclidine (PCP) or MK-801, and blockade of the disruption of prepulse inhibition by indirect or direct DA agonists or NMDA receptor antagonists. Atypical and typical antipsy-chotic drugs are active in all these models, with atypical antipsychotic drugs, apparently because...

Pharmaceutical research into the identification of subtype selective 5-HT2C agonists has been an ongoing effort since the mid-1990s, driven largely by the potential of such drugs to treat obesity (Nilsson 2006). This has not been an immediately successful enterprise, largely because of the high sequence homology between the 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes (Hoyer et al. 2002 Barnes and Sharp 1999) and the negative impact of direct 5-HT2A and 5-HT2B receptor activation. The...

5-HT2CR mRNA is prominently expressed in the striatum (Str) and nucleus accumbens (NAc) (Eberle-Wang et al. 1997), two subcortical regions vital for coordinating many important behaviors such as motor program selection and responses to appetitive stimuli. The Str and NAc also play vital roles in how the phenotypes of Parkinson's disease and substance abuse, two highly morbid and difficult-to-treat clinical conditions, are expressed. Studies of basal ganglia physiology and behavior in 5-HT2CR...

From an evolutionary perspective, reinforcement of natural stimulation that enhances survival or the perpetuation of genes (such as food and sex) would be beneficial to the continuation of the species. The system of conditioning through reward and gratification remains one of the most fundamental examples of such reinforcement. However, there is a small fraction of pharmacological substances that possess the ability to abnormally intensify this reward function in the brain, known as drugs of...

The 5-HT2C-selective receptor agonist, WAY-163909 12 1,4 diazepino 12 indole ,was reported to be active in various animal models of schizophrenia (Marquis et al. 2007). At doses of 1.7-30 mg kg IP, it decreased apomorphine-induced climbing and behaved like an atypical in that it did not cause catalepsy. Similar to 5-HT2A antagonists, e.g., M100907, WAY 163909 (0.3-3 mg kg subcutaneous SC ) was reported to be more effective in inhibiting PCP-induced locomotor activity than d-amphetamine with no...

Serotonin, by activating different receptor subtypes, regulates membrane excitability in the central nervous system in a complex manner (Andrade 1998). The involvement of various voltage-gated ion channels in this action of serotonin receptors has been demonstrated (Carr et al. 2002 Colino and Halliwell 1987 Haj-Dahmane and Andrade 1996 Penington and Kelly 1990). However, application of a low concentration of a 5-HT1A or 5-HT2A 2C agonist alone fails to alter the action potential firing...

There are several lines of evidence suggesting that GPCR dimerization occurs prior to receptor expression on the plasma membrane. The most notable example involves heterodimerization of class C GABAbR1 and GABAbR2 receptors, which has been demonstrated to be essential for receptor trafficking from the ER to the plasma membrane (Jones et al. 1998 Kaupmann et al. 1998 White et al. 1998 Margeta-Mitrovic et al. 2000). Dimerization has been proposed as a general mechanism necessary for proper...

Prader-Willi syndrome is a congenital disease with an incidence of about 1 in 8,000 to 20,000 live births. Prader-Willi syndrome is the most common genetic cause of marked obesity in humans. The excess weight causes type II diabetes as a major complication. This makes PWS the most frequent genetic cause for type II diabetes (Butler et al. 2006). Early PWS is characterized by a failure to thrive, feeding difficulties and hypogonadism. Later, the patients are characterized by short stature and...

The constitutive activity of seven-transmembrane receptor is a concept now widely accepted and well characterized in heterologous recombinant systems in vitro Costa and Herz 1989 Milligan et al. 1995 Berg et al. 2001 Kenakin 2001, 2004 . The capacity of this receptor to regulate cellular signaling systems in the absence of occupancy by a ligand could be considered as an artificial property as it depends on the density of the receptor at cell surface and the total absence of the endogenous...

The 5-HT2 receptor family seems to be particularly involved in anxiety because several drugs effective for the treatment of anxiety disorders interact with this type of receptor Mora et al. 1997 Peroutka 1995 . Mora et al. 1997 tested mCPP, ritanserin and propen-1-yl phenol hemifumarate SR-463496A , a selective 5-HT2A 2C receptor antagonist Rinaldi-Carmona et al. 1992 on two types of fear. The authors used a paradigm in which the same rat in one experimental session was exposed to two types of...